Saturday, 28 February 2015

How are your creative skills? Can you come up with a better name than HEART? #CrowdSpeak #MSBlog #MSResearch"Since launching our crowdsourcing project and proposing the anti-EBV/HAART study we have a few complaints about the acronym HEART. Can you come-up with something better? Something more catchy?"

"Our survey remains open and we have expanded the number of questions to include a suggestion for a new name."

How to prevent getting worse when stopping natalizumab. #ClinicSpeak #MSResearch #MSBlog"A critical issue in MS with regard to risk:benefit assessment of DMTs (disease-modifying therapies) is the short-change we give to the risk of MS. This real-life data study below shows that when we de-risk PML by taking MSers off natalizumab, we increase their risk of becoming more disabled. If you are on natalizumab and stop the drug your have two-fold higher risk of getting worse compared to MSers who stay on natalizumab. More importantly if you stop natalizumab you are likelihood of having an improvement in disability plummets and is 68% lower than MSers who stay on natalizumab.""This study is telling us several things:

How are expectations have shifted since we have licensed high-efficacy DMTs; we are not only expecting MSers to flatline (no increase in disability), but expect a significant proportion of MSers to have a sustained improvement in disability.

Your baseline disability level predicts worsening. In other words if you have lost time, or brain, you are more likely to progress when coming off natalizumab. This makes sense biologically. What protects from developing progressive MS is reserve capacity; if your nervous system has not lost too many neurons and axons the surviving cells have the ability to compensate.

Natalizumab is not an induction therapy; it is a maintenance therapy. In other words when you stop natalizumab MS comes back with a vengeance. Some observations suggest the rebound with natalizumab is much worse than you would expect from natural history studies. Natalizumab is an interesting observation.

Should we accept these results? No. I think there are now several strategies that we can adopt to prevent rebound and worsening post natalizumab. This study was done in the era when we did wash-outs and allowed rebound to occur post-natalizumab. I think most of us will not simply stop natalizumab without transitioning MSers onto other high-efficacy therapies. I have posted on this before."

OBJECTIVE: The objective of this paper is to estimate the risk of reaching well-established disability milestones after withdrawal of natalizumab (NTZ) due to concern about the risk of progressive multifocal leukoencephalopathy in MSers.METHODS: Data from 415 MSers followed-up for six years after starting NTZ were collected from seven tertiary MS centres. The risk of disability worsening, i.e. reaching Expanded Disability Status Scale (EDSS) scores of 4.0 or 6.0, and the likelihood of experiencing a disability reduction of one EDSS point (or more), were assessed by propensity score-adjusted analyses in MSers who discontinued and in those still on treatment at the end of follow-up.RESULTS: A total of 318 MSers who received standard NTZ treatment without experiencing evidence of disability worsening in the first two years were included in the six-year follow-up analysis, with 196 (61.6%) still on treatment and 122 (38.4%) discontinuing after a median time of 3.5 years. MSers in the discontinuing group had a more than two-fold increased risk of disability worsening (p = 0.007), and a 68% decreased likelihood of experiencing disability reduction (p = 0.009) compared with the continuing group.CONCLUSION: While discussing the overall risk/benefit profile of NTZ, MSers should be advised that, in case of treatment discontinuation, the risk of disability worsening is one in three, and increases to one in two if the EDSS score at NTZ start is above 3.0.CoI: multiple

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of grey matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by MRI. The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified 9 areas showing different thickness between cases and controls (regions of interest, ROI) (8 of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for sub networks enriched with nominally associated genes and searched for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signalling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS.

We are a product of our genes and Genome Wide Association Studies (GWAS) have so far found about 150 MS Susceptibility genes or gene products. In this study they looked for pathology and notably MRI-detected Grey matter thickness as a marker of cognitive disability and found no associate with any single gene. It has been said that unless you examine thousands of samples you get nothing that is reproducible. This what was found.

However if you look at networks of gene they found associates that influenced calcium levels (we know if you have too much calcium it triggers cell suicide). Excessive glutamate levels trigger calcium excessive calcium concentrations within the cell that can lead to cell death. These will all need to verified in additional studies, but already we have been thinking about blocking glutamate signalling.

In animals, blocking excessive glutamate signalling can slow progressive nerve loss however this is associated with significant side-effects and also the system is rapidly de-sensitized, so drugs don't work. So far in MS this approach has not worked..I won't say I told you so, but I could have told you so.

Friday, 27 February 2015

What is the rationale behind the HEART trial? #CrowdSpeak #MSBlog #MSResearch"Some of you have asked about the scientific rationale behind Charcot 2. If you have been reading this blog for sometime you will have noticed a theme emerging around viruses and MS. There is now compelling evidence that EBV and HERVs (human endogenous retroviruses) are involved in MS. Some of us in the community are of the opinion that EBV causes MS and that if you can prevent people becoming infected with EBV you may prevent MS. How EBV causes MS is not known and there are as many theories as there are investigators working in the EBV-MS field. I personally don't know how EBV causes MS. One of the theories that we are investigating is that EBV causes MS via its interaction with HERVs.""HERVs are viruses that live in our genome; about 6-8% of the human genome is HERVs. Why do we have so many HERVs in our genome? Evolution has selected for them because they must give us, and other mammals, a survival advantage. For example, one HERV protein is critical for the development of the placenta. Mammals who don't have a placenta (marsupials) don't have this HERV. As HERVs are sort of 'foreign', the human body has developed intricate ways of detecting them and if they are found to be expressed in a cell the cells immune system flags that it is infected with a virus so that the immune system can eliminate the cell. This so called danger signal is often is what is needed to activate the immune system and if this happens to be an autoreactive immun cell it can trigger autoimmunity. Interestingly, there is a very rare disorder due to mutations in the systems that detect and suppress HERVs in cells. The children with these mutations present with multiple autoimmune diseases indicating that uncontrolled HERV expression can drive autoimmune disease. You may be aware by now that there is emerging data that MSers have evidence of increased HERV expression in the cells of the peripheral blood and possibly in their brains as well. At present we don't know if MS causes HERV expression or does HERV expression cause, or drive, MS? This is why we have launched the Charcot project.""So how do EBV and HERVs relate to each other? It turns out that herpes viruses, in particular EBV, are potent transactivators of HERVs. In other words EBV does something to wake-up the sleeping HERVs in our genome and increases their expression. This is the rationale for using drugs to reduce EBV activity in the hope they will suppress HERVs, or even better drugs that target EBV and HERVs.""Why HAART (highly-active antiretroviral therapy)? This is based on our anecdotal evidence that MSers who have become HIV positive and go onto HAART do well regarding their MS. We agree that one, or two, or even three, swallows don't make a summer, which is why we have done other studies to try and confirm these observations. What we have shown is that people who are HIV-positive and go onto HAART have a low risk of getting MS. The longer they are on HAART the lower their risk of getting MS is. We are not the only ones to observe this; the Danes have made a similar observation in their country. We have also asked the Swedes, the Kaiser Permanente (California) and the Veterans Administration (US) to look at their databases to see if they can confirm our observations. The big question is it the HIV virus or the HAART that is lowering the risk of MS? We don't know.""However, once you make an observation like this you can't ignore it. This is why we have done the INSPIRE trial using raltegravir an antiretroviral drug that blocks the integration of retroviruses into the genome. Raltegravir is a relatively new anti-retroviral, and was only launched in 2009 and only becoming widely used in the UK to treat HIV-1 infection from 2011. The latter is important because our observations of HAART lowering the risk of getting MS was from the pre-raltegravir period. Therefore, regardless of whether or not the INSPIRE trial is positive we need to test HAART as a potential treatment for MS.""I am aware that what I am saying above is complex, but I hope it sets out the rationale and makes the case for using both and anti-EBV drug and HAART in MS and more importantly for using them in combination. The proposed HEART study below is simply and enabling study to provide us with necessary virological and safety data to make the case for doing a larger efficacy study in MS."

"As you can see there are many questions that need answering and we would like your input to answer them. The purpose of this study is to explore whether or not our candidate drugs do what the meant to do to on the target viruses in MSers and to show that there are no major safety issues. Further thoughts please?"

"The survey is still open and we have expanded the number of questions we are asking; we need more responses in relation to the type of funding model and whether or not you you understand what we are trying to do."

"Please note although we are going with the Charcot 2 Project we are still working on the HSCT vs. Alemtuzumab or the ZEUS study. At the moment we are engaging with Dr Paolo Muraro's group at Imperial who will need to lead on this."

BACKGROUND:An association between working shift at a young age and subsequent risk for multiple sclerosis (MS) has been observed.OBJECTIVE:To investigate whether this finding could be replicated, and to further explore the influence of age at first exposure to shift work.METHODS:Using a Swedish population-based, case-control study (2337 cases and 4904 controls), the incidence of MS among subjects whom had worked shifts was compared with that of those whom had not, by calculating odds ratios (ORs) with 95% confidence intervals (CIs) by means of logistic regression.RESULTS:The OR of developing MS was 1.5 (95% CI 1.2-1.8) among those whom started working shifts before age 20, whereas a less pronounced association was observed among those whom started working shifts at age 20 or later (OR 1.2; 95% CI 1.1-1.4). The effect of shift work was more pronounced among subjects whom had been exposed at a young age, regardless of the duration between the start of shift work and disease onset.CONCLUSION:Some aspects of adolescence seem to be of great importance, regarding the impact of shift work on MS risk. Circadian disruption and sleep deprivation may contribute towards explaining the association; however, the exact mechanisms behind our observations remain to be elucidated.So we have smoking, sunlight exposure, toxic chemicals and this one suggests shift work so this study suggests that if you did shift work then you are more likely to get MS 1.2 times more likely. This is small risk and many if not most of you will never done shift work. However I suggest we do not avoid all shift work but sign up to the community of Shift.ms (if it is the place or you)

The use of Tumor Necrosis Factor alpha (TNF--α) antagonists has profoundly improved clinical management of psoriasis and other inflammatory diseases, but acute and chronic adverse reactions, including demyelination, are becoming increasingly recognized. We reported a case of multiple sclerosis in a 48--year--old Italian man with plaque psoriasis treated with etanercept. Through a literature review, we found a total of 35 psoriatic patients, including our case, in whom a demyelinating disease developed in course of TNF--α antagonists therapy. Since neurological disorders are rarely associated with the use of anti--TNF--α therapy in psoriatic patients, but have severe side effects, physicians should screen patients before starting therapy, excluding a positive anamnesis for demyelinating disease;; if patients receiving anti--TNF--α drugs develop new or unusual neurological symptoms, the anti--TNF--α drug should be stopped and patient should be properly examined. Furthermore, therapies for demyelinating diseases that could exacerbate psoriasis manifestations should be carefully avoided.Tumor necrosis factor is a central mediator in inhibiting arthritis but if you inhibit TNF in MS it can make MS worse. In other conditions it can give you MS as shown in this study.However in animals the jury is out and blocking TNF can do good things and it can do unwanted things,it depends on the context.In animal studies mechanism of action is all important an in yesteryear (before they did the studies in MS) it was said TNF is bad so block it and there are a number of drugs that were claimed to inhibit TNF. However now this idea has been questioned and blockade of TNF can make MS worse so should we be using them in MS?What do you think and what would you think if I said they are being tested in MS?

Thursday, 26 February 2015

What do you think about the HEART trial? Have your say. #CrowdSpeak #MSBlog #MSResearch"Thank you for engaging with the our tentative exploration into the Crowdfunding space. It looks as if the Charcot Project has the most support. As this initiative is to enable a second phase 2 trial targeting both EBV and HERVs (human endogenous retroviruses) in MS we have made a start on preliminary trial design. As you can see there are many questions that need answering and we would like your input to answer them. Please note this study is simply being done to provide necessary pilot data so that we can make the case to a traditional funding agency of the need to do the trial. The purpose of this study is to explore whether or not our candidate drugs do what the meant to do to on the target viruses in MSers and to show that there are no major safety issues. Thoughts please?"

"The survey is still open; we need more responses in relation to the type of funding model. Please note although we are going with the Charcot Project we have not given up on the HSCT vs. Alemtuzumab or ZEUS study. For the latter to happen we need to involve a large number of other people. We have already started bringing people together to test the waters and appetite for the ZEUS study."

Multiple sclerosis (MS) is a neurological disease mostly affecting women of childbearing age. When counseling MS patients, many questions arise on the reciprocal influence of MS and pregnancy. However, little is known on the impact of MS and its treatments on the time to pregnancy. The objective was to evaluate fecundity (pregnancy and time to pregnancy) in a French cohort of MS women. One hundred and fifteen women with MS were included consecutively in this observational retrospective study. Pregnancy and time to pregnancy were collected using self-questionnaires. Among the 115 patients, 216 pregnancies (from 84 women) were reported. Mean time to pregnancy, which was available for 124 of these pregnancies, was 8.57 months when pregnancy occurred before MS onset, and 7.53 months after MS onset. Among the 95 patients who had a parental project, 2.27 spontaneous pregnancies per woman were recorded. The mean number of children per woman with MS was 1.37. Spontaneous pregnancies per woman and time to pregnancy were not different from the general French population. However, despite a normal fecundity, the mean number of children per woman with MS (1.37) was lower than in the general French population (1.99)

This French study looks at whether MS affects your ability to get pregnant and the take home message it that it does not, but people with MS tended to have fewer children and is no doubt influenced by people who decide not to have kids.It is important that you discuss pregnancy with your care team, as certain treatments have risks for the the unborn

Some people think that animal studies should be like clinical trials and registered in a public data base before the work is done. This was the idea at a science meeting that I have recently attendedIf you are a research scientist you would have to say what you are doing before you do it, what would be the primary outcome that you want to find and you would say how you are going to do it so you would stop scientists P-hacking, which is dredging the data with lots of tests until you find something interesting and it would stop Harking, which would be creating the hypothesis after you have actually done a study....

Why do registration? Some people argue to find the missing studies because the published animal data is overwhelmingly positive and suggests that the negative stuff never sees the light of day, so it is biasing the view such that drugs are better than they actually are. Why were the studies not published....presumably because they don't work. If this data was evident would this allow us to pick better candidates to try in MS. Furthermore having the information in the public domain would mean that the animals were not used in vain.Some journals are offering to review the study before it is done and they will agree to accept it irrespective of whether the study works or not. This is designed to reduce the bias associated with positive studies. However, it seems that it is not necessarily the journals that are not publishing negative data ,but authors are not bothering to try and publish negative data, because of the time and cost and effort needed to publish papers.

Time and time again we see rubbishy EAE data that won't be reproduced in another animal study let alone in a human. However, the big journals are part of the problem and are full of the non-reproducible stuff. It may come as a surprise you that about a third of published studies in the top journals apparently cannot be reproduced at all, a third give a partial answer and a third seems to be OK.

People do not always agree with what we find but we try to get the right answer..even if it means we may not get the first answer.

Will registration of animal studies make us find drugs useful for humans, I am not sure this is where the problem with translation of animal studies lies and registration would require a lot of effort.Maybe we need a depository online, where we can show the methods and results (& raw data) of experiments (without comment would be fine) that don't work, or even that do work and reproduce the study. Possibly this can be linked to the DOI of the paper whose data can't or can be reproduced maybe the "The Power to Reproduce" or "The negative experiment" housed on a reputable site e'g NIH). Maybe this could be a way such that dogma will not build up as quickly and unreproducible work can be quickly refuted. It is often hard to get papers published that disagree with published work taking years to achieve....this was evident when we tried to publish data where we were disagreeing with the conclusions of our own work that we had made earlier.Are these mad ideas? Are they practical?I try and tell people who are reading science papers that they need to be aware of the CONSORT and ARRIVE Guidelines which are guidelines how to report human and animal studies. It helps you to assess quality of the experiment and believability of the data. When I teach about the ARRIVE guidelines, I try and use real examples to show why they are worthwhile to consider.So a registryMany years ago I did an experiment that I did not publish showing that I could not repeat the contents of a Nature paper. This lack of effect was reproducible, but rather than waste more time and money doing more work to try and publish a negative paper, I dropped the approach and moved on. I subsequently heard that four other labs had done the same. If there was a place where we could have pinned up the data, the readers could have made up their mind and the neuros too, as the approach did not work in MS.Had the studies being registered we would be aware that four other labs had done the study. Why no papers on this proposal. However if there was a site where we could have linked the data to DOI of the paper and included the data, people could see how many animals were used, the negative/replication data is in public domain and available for meta analysis or analysis by the original group.P.S. The World wide web did not exist when the experiments were doneRegistration....Would Pharma do it...I doubt it because they would not be willing to say what they are up to publically before they do it. Why because it would disclose the idea before the patent, so nothing would get developed....They, or your science competitor with more resource to do the experiment you have alerted them to, will laugh at dozey academics giving all their ideas away for free, years before your competitors would know...is this a good thing? Some of the old data does eventually surface in publications

BACKGROUND: An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients.OBJECTIVE: To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS.METHODS:The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes.RESULTS: Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change.CONCLUSIONS: In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect.

Trichuris Suis is the pig whipworm and some neuros have been infecting MSers with them. The idea comes from people supporting the hygiene hypothesis so by infecting people with worm eggs it would drive a disease-causing TH1/Th17 response to an immunosuppressive Th2 response blocking MS. In this study the people infected produced eosinophils, which are a cell that kills parasites and is indicative of the Th2 type response. However, there was no evidence that MS was suppressed.

Studies in EAE have been used to build up the idea Th1 response bad, TH2 (&B cell response good. This may work with an immune response that only lasts 2-3 weeks and generates before pathogenic antibodies are around to cause problems as occurs in most EAE models. But we work with EAE that doesn't fizzle out after one attack and B cell responses become more prominent with time. The mantra we have worked to is TH1 bad and TH2 ( & B Cell) response bad too. We don't want either.

As I have said before and will say again, Throughout the 1980's and before, worm infections were common place in most University animal houses and there was no problem with animals getting EAE, so maybe worm eggs are not that good as immune modulators?

Should we adopt an all-or-nothing crowdfunding model? #CrowdSpeak #MSBlog #MSResearch

"The following article in last month's Nature Medicine summarises very succinctly what is happening in the crowd-funding space. It looks as if we are coming to the party late and playing catch-up. I have highlighted some key aspects in bold in excerpts from the article. Based on our survey responses to date appears that the Charcot Project is ahead of the Zeus Trial. A new question that I have added to the survey is whether or not we should adopt an all-or-nothing model of funding. In other words if we define a target should we only start the project if we reach the target or should we use the money to help prime a traditional grant application?"

..... trend of crowdfunding has extended beyond general projects, such as those usually found on Kickstarter and Indiegogo, into scientific research, perhaps in part because reduced government spending on science has many biomedical researchers looking for new sources of financial support. With the help of science-specific crowdfunding websites such as Consano.org and MedStartr, researchers are increasingly turning to the public to help bridge the gap between drug development and its implementation in the clinic......
....... But the more recent emergence of this trend in financing clinical trials—organizations such as Cancer Research UK and the newly established Give to Cure Foundation are establishing crowdfunding campaigns specifically intended for clinical trials—raises questions about whether donors or foundations should have the ultimate say in which trials get funded.......
...... Even well-established foundations, such as the London-based Cancer Research UK, have seen the potential in being open with their donor bases. In 2009, the organization launched MyProjects, a concept centered on users being able to direct their donations to a specific cause. When people arrive at the website's main page, they are given the option of choosing from a variety of causes to support, including research into specific types of cancer, basic biological experiments involving tumors and also clinical trials of potential cancer drugs......
..... “One key thing is tangibility,” says Catherine Ferguson, Innovation Project Lead at Cancer Research UK, “It's an inherent part of crowdfunding that isn't inherent in regular funding.” Whether it's a particular type of cancer or a particular therapy, crowdfunding allows for a “more direct relationship with both the researcher and the research,” she adds, emphasizing that this directed approach is good for maintaining relationships with donors.......
...... In December 2014, Cancer Research UK completed its first formal crowdfunding campaign. This campaign was intended to support three different projects, one of which was a clinical trial aimed at testing a vaccine against the Epstein-Barr virus in cancer patients. None of the projects reached 100% of its funding goal, with the clinical trial project only raising about 6% of its £40,000 ($61,000) goal, but the organization chose a so-called fixed-funding model, in which they chose a goal amount but kept none of the funds that were raised if the goal wasn't met. “It felt disingenuous to keep some of the money but not make the research happen,” said Ferguson. “We really wanted to emphasize that the money was for a specific project and if the project couldn't be fully funded, then why keep the money?” Because the campaign wasn't successful, the funds raised were returned to those who pledged the money, but Ferguson said that many of the donors reached out to make contributions to the organizations anyway.......

..... Not all organizations are opting for an all-or-nothing model. ALS Worldwide, a Wisconsin-based nonprofit that offers support to people and families affected by amyotrophic lateral sclerosis (ALS) and funds research into the disease, launched a crowdfunding campaign in October 2014 for a clinical trial of microneurotrophins, smaller versions of proteins that assist in the development, growth and function of motor neurons. The campaign is hosted on Indiegogo, the same platform used by Cancer Research UK for its campaign, but ALS Worldwide opted for a flexible-funding model in which they can keep whatever funds are raised, even if the goal isn't met.......
....... “It's an excellent thing that science is funded by ordinary people, says Jai Ranganathan, director of SciFund Challenge, a nonprofit that encourages scientists to engage with the public but also helps them crowdfund research. “There's a perception that [federal] money comes from the heavens, but it comes from taxpayers,” which is the ultimate form of crowdfunding, he added......
...... Directed and transparent fundraising allows those who want to be engaged in the scientific process that opportunity. To Ranganthan and other champions of crowdfunded science, engagement with the public is more essential now for science itself. “What is going to keep government funding coming is people engaging with the scientific process,” he says......
....... But for others, like Terry McGlynn, a biology professor at California State University Dominguez Hills, the level of engagement necessary for successful crowdfunding often requires a luxury of time and money. “I have misgivings about the fairness of crowdfunding campaigns,” he says. “The breadth and wealth of your social network shouldn't determine whether your research gets funded or not.”
...... Ultimately, for those attempting to raise funds, crowdfunding allows them to reach a different section of the audience than might otherwise have donated. “Our donors tend to be older and predominantly female,” says Greg Jones, senior press officer at Cancer Research UK, “but we found that with crow-funding, it's younger males that are more involved.” And for those who are trying to raise funds through any means possible, reaching a different slice of potential donors is enough incentive to give crowdfunding a try......Crowdfunded clinical trials are still nascent. “It's an area we're going to continue to explore,” says Ferguson. “We know that there is an appetite and opportunity for it, but it's a matter of figuring out the right way to go about it.”

"The following are the two projects we have proposed based on interactions with you on the blog. At present the Charcot Project has the most support. This does not mean we can't help kick-start them both."

HSCTThe proposed ZEUS trial below has had a lot of interest from you the readers. To get this project off the ground, and funded, we would need to explore the community's attitude to the trial and whether it is addressing an unmet need. Exchanges and surveys done via this blog are not necessarily representative of the wider community. We as a group have no expertise in HSCT and we would therefore need to include groups and centres that do have expertise. Paolo Muraro's group at Imperial College would be a natural fit us. In fact Paolo has expressed an interest in leading this trial.

What we would need to answer are the following list of questions:

Do MSers understand the immediate risks associated with HSCT?

Do MSers understand the undefined risks associated with HSCT?

Would MSers be prepared to be randomised to receive alemtuzumab or HSCT?

Would British Neurologists be prepared to refer patients for a HSCT trial?

Do haematology units in the UK have enough capacity to handle a large national MS-HSCT trial?

What are the economics of HSCT? How do they compare to alemtuzumab treatment?

Would a non-myeloablative or a myeloablative protocol be best?

What is the optimal trial protocol?

Would we only target DMT failures or MSers naive to DMTs?

Would eligible MSers have to have highly active MS or just active MS?

Would the NIHR or MRC be prepared to discuss funding a trial of this nature?

Etc.?

Charcot ProjectWe as a group would want to focus on targeting both EBV and HERVs (human endogenous retroviruses) with antivirals in MS. Before doing a formal clinical trial we would need to do a small exploratory study using a combination of anti-EBV and anti-retroviral drugs. The primary outcome of the study would be to makes sure our anti-EBV drug is safe in combination with HAART (highly-active anti-retrovirals) and whether the combination were suppressing both EBV and HERV activity within the body. We would propose doing a small open-label study of approximately 20 MSers looking at EBV shedding, and EBV viral loads, and HERV activity in the peripheral blood before and after treatment with the combination of anti-virals. If positive data from this enabling study would be used as part of a grant application to fund a phase 2 trial assessing the efficacy of combination antivirals on MS disease activity. Ideally we would want the phase 2 study to be a parallel design placebo-controlled double-blind study, rather than the cross-over study we have just completed for raltegravir (INSPIRE TRIAL).
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"This is a community project so please feel free to comment. Thank you."CoI: multiple

Six inspirational but everyday heroes and heroines have been confirmed to take part in BBC One’s The People’s Strictly for Comic Relief and fulfil every Strictly fan’s dream.Whilst we should remain impartial...sod it..Come On Trishna!For a Non-British Audience how do you describe Peoples Strictly.

Well it is a twist of a television light entertainment show called Strictly Come Dancing (Click HERE), where they pair a celebrity with a professional dancer to make a fool of themselves for the joy of the British Public. Doing the Jive, Cha, Cha Cha, Tango etc. This is a throw back of a (truely awful-from a personal perspective..but my hips don't move:-) programme called Come Dancing (Click Here), which was a Ballroom Dancing Competition, with a twist from a film on dancing called Strictly Ballroom.
However as this idea has been spun out to 40 countries you may know it by another name such as "Dancing with Stars".
So it is with People Strictly....but the stars are not celebrities, the stars who have done something for the community. Out of thousands of applicants 6 people have been selected.:

Philip Barnett from Cornwall, who founded a children’s theatre charity in 1994 and has since raised over £2 million and staged over 70 shows.

Trishna Bharadiafrom Buckinghamshire, who is living with MS and works hard to raise awareness around the condition.

Anna Kennedy OBE from Middlesex, who set up the largest school for autism in the UK after her own autistic sons were turned away from mainstream education.

Cassidy Little, originally from Canada but now lives in Peterborough. Cassidy was serving in Afghanistan as a medic for the Royal Marines when he was severely injured, losing the lower half of his leg in an explosion. His positivity has helped several of his colleagues through their time in rehab.

Heather Parsons from Hampshire, who set up her own charity to support intensive care patients and their families, following her own near-death experience in intensive care.

Michael Pattie from Dumfries, who has raised over £300,000 for meningitis charities, after losing his son to the disease

Each contestant has been paired with a professional dancer from the Strictly Come Dancing family. They have spent five weeks being immersed in the Strictly experience, as they prepare to become the new stars of the ballroom.

The series will consist of four pre-recorded programmes, and the first two heart-warming episodes (Screened 25th February and 4th March) will introduce the contestants as they get the surprise of their lives and discover that they are about to embark on an incredible Strictly journey.

The third episode (5th march) will continue to follow their training and preparation as they get ready for their ballroom debut in front of the nation.

Episode four (11th March) will see all six contestants compete on the famous Strictly Come Dancing ballroom, as they vie for the judges’ scores and viewers’ votes. The judges’ scores will be for guidance only, and the public will have the deciding vote.

The Training is gruelling and fingers crossed the Fatigue and Stress won't kick-in too much. I understand the Beeb has been very understanding

Voting lines will open once all couples have danced and the winner of the public vote will then be crowned The People’s Strictly champion as part of the live Comic Relief show on BBC One on Friday 13 March 2015.

Comic Relief is an operating British charity, founded in 1985 by the comedy scriptwriter Richard Curtis and comedian Lenny Henry in response to famine in Ethiopia.The highlight of Comic Relief's appeal is Red Nose Day, a biennial telethon held in March, alternating with sister project Sport Relief. This fund projects in the UK and in many other parts of the world.

Whilst all the contestants deserve heaps of praise, lets get behind Trishna our Expert MSer, who is part of TeamG.

Everyone besides ProfG had never Blogged and to be honest we had not even looked at ProfGs handy work.(Remember he used to post about once in a blue moon). However, Alison (Our Designer PhDer) & Becky (from Shift MS) dragged the Team into the Social Media world of the Twenty first century. Trishna and her Mum were judges of our presenting skills and helped us with our public engagement activities. Can you remember our Question Time?

Trishna contributes to TeamG activities including being one of our Expert MSers, who is embedded in our teaching, clinical and research activities. She also runs Asian MS, which is associated with the MS Society

You can watch starting Today BBC1 (British Broadcasting Corporation) at 21.00 and who knows who else you may see:-).

As soon as we published the prospect of developing a new drug for symptom control.You said "As Del Boy (Prof G) said to Rodney (Prof M) - we'll be millions. I better invest in beer companies and heavy metal record labels for when you hit the big time. Prof G can give his countryman Berlosconi a run for his money".Maybe we are psychic, as I made this figure last weekend. Enjoy:-).

What can we say..not a lot...it is a contractual secret thing. This is

Tuesday, 24 February 2015

MD2 in response to a comment recently (16:2:2015) wrote "we have some great research coming down the pipe that will stick two fingers up to the negative crowd;-)"

Today is the part of the proof ...but these two fingers are not exactly the response I was thinking:-). But with this attitude...hey let's rock:-).p.s. Non-Brits may not get it...best left that way:-) p.p.s. This is a Joke! Before some people get too offended (http://news.bbc.co.uk/1/hi/8687002.stm)

Many blog sites get conned into doing advertising for Company X or Company Y following press releases by announcing that Company X or Company Y, will start trials in MS as soon as they have financing, hoping for some more shareholder investment.

So now is the time to make a company pitch, but we are not after your money, but we will be after your help!

We do not generally make Pharma Plugs, but as this the culmination, so far, of our research, it is time to blow the premature trumpet following a recent press release.

In 2001/2002, whilst at University College London (UCL) we (MD/MD2) started a project with some UCL chemists (led by Prof. Dave Selwood) to make a symptom control drug that does not have the side effects of current anti-spastic drugs. We have generated one that works in animals, as well as other anti-spastic drugs, but does not appear to have their sedative side effects.

In 2005 we spun out a virtual company (Canbex therapeutics) to manage and develop the drug, no staff just extra work. Through a lot of help from venture arms of Charities we have moved it forward, bit by bit, helped by discoveries made at Queen Mary University of London and elsewhere and with the help of ProfG. We took on a business management team (Click) and in 2013 we finished our animal safety studies. In 2014 we completed our double-blind phase I safety tests in humans (80 volunteers at a phase I testing centre linked to Kings College London) with a solid green light that showed the drug was tolerable and safe. Today, we have received the necessary investment from a company, which makes anti-spastic drugs, that will allow us to bring this drug to people with MS. Ipsen will then have the option to acquire Canbex for subsequent development. In the next few weeks/months we will be ready to start phase II studies in spasticity in MS. If you are eligible we hope you will consider volunteering for the trial.

We haven't had the money to pay for a wacky name, like QmucleonTM, (apparently this can cost pharma between $1000,000-$700,000) at present it is simply the sixteenth drug that Cristina Visintin made....called VSN16.To give you an idea about this drug, as the work is unpublished, so far:
(a) It is a pill (currently in a capsule) (b) It appears to be safe and tolerable (so far CLICK)(c) It has a new mechanism of action (which we know)(d) It is TeamG research Bench to Bedside.

Spasticity is a problem that often starts early in MS, but doesn't really get treated until spasticity is more advanced because of side effects, we want to plug that gap and replace current meds.

We have a novel rapid trial design planned, after which time the project will be a success and we will need longer studies or it will have failed. Results early 2016, provided we get enough volunteers. We will be looking to recruit soon (a couple of months). If you are eligible (to be announced), we hope you can help.Some of you don't like the personal stuff, so switch off now.

You asked about breakthroughs for this year, is this one? (To us it really seems like one, Very few academic scientists ever get a treatment to humans and even fewer are on board for the whole voyage ).......but is it a breakthrough? no, not yet (until we know if it works), but to all those who like to say we don't do any useful research....it is time to respond and I would like to say.......Ouch:)......slapped wrist:-)......the tortoise with no legs is on the move and has seen off a couple of hares already!

The wheels may come off, but at least we are trying:-). reallyCoI: Members of TeamG are founders and Shareholders of Canbex

Special thanks to:

FastForward (NMSS-USA) who had the faith to help us cross the "Valley of Death"

"The case study below of a lactating MSer treated with high-dose intravenous steroids for a relapse shows that only a small amount of the actual steroids crosses over into the breast milk. The actual dose the baby gets from breast feeding is low. Women MSers who want to start or extend their families will find this small bit of evidence reassuring."

"You are probably already aware that during pregnancy the attack rate of MS falls, particular in the middle and last thirds, with a rebound post-partum, or after delivery. Breast-feeding seems to blunt the rebound after delivery. Managing MS in pregnancy is quite an art, in particular in woman who are a DMT and want to fall pregnant. None of the drugs are recommended by manufactures to be used in pregnancy hence we have to rely on data collected in registries and from animal studies to ascertain which drugs are safe in pregnancy. At the moment glatiramer acetate, and possibly interferon-beta and dimethyl fumarate, appear to be safe in pregnancy. Natalizumab is emerging as being relatively safe with an increasing number of woman falling pregnant having good outcomes on the drug. Alemtuzumab, and other induction therapies, are probably the most appealing as they are given as short courses and are out of the system quite quickly making them safe in pregnancy. The latter is provided you are not pregnant whilst having the induction course. The one caveat with alemtuzumab is secondary autoimmunity; the auto-antibodies can cross the placenta and cause transient autoimmunity in the unborn child. The latter is a particular problem with thyroid disease; hence all woman of childbearing age who opt for alemtuzumab therapy need to be told of the risks of autoimmunity to the unborn child. My endocrinology colleagues tell me that transient neonatal hyperthyroidism is quite common and is usually quite simple to managed. Based on my limited experience to date the risk of transient neonatal autoimmunity has not affected decision-making with regard to being treated with alemtuzumab."

"Pregnancy and MS is complex and expanding topic and is almost becoming a sub-specialty on its own."

Background: High-dose intravenous methylprednisolone, a glucocorticoid with powerful anti-inflammatory activities, has become increasingly important in treating acute relapses of MS.

Case report: This is a case report of a 36-year-old lactating female who was receiving a 3-day course of high-dose methylprednisolone (1000 mg IV) to treat MS. Breast milk samples were obtained at 1, 2, 4, 8, and 12 hours following a 2-hour intravenous infusion on days 1, 2, and 3. The relative infant dose was found to be 1.45%, 1.35%, and 1.15% for days 1, 2, and 3, respectively. Using the average measured concentrations (Cavg) for days 1, 2, and 3, the estimated infant exposure was 0.207, 0.194, and 0.164 mg/kg/day, respectively, which is below the recommended dose given to neonates requiring methylprednisolone drug therapy.

Conclusion: Infant exposure is low and mothers could continue to breastfeed if treatment with IV methylprednisolone is very brief. However, if the mother wishes to limit infant exposure further, she could wait 2 to 4 hours after IV methylprednisolone administration, thus significantly limiting the amount of drug in the breast milk.

The introduction of the McDonald criteria has enabled earlier diagnosis of multiple sclerosis (MS). However, even with the 2010 revised criteria, nearly 50 % of patients remain classified as "possible MS" following the first MRI. The present study aimed to demonstrate that time to MS diagnosis could be shorter than 2010 revised criteria, and established after a single early MRI in most patients with the association of the symptomatic lesion and at least one suggestive asymptomatic lesion. We also evaluated the short-term predictive capacity of an individual suggestive lesion on disease activity. We analyzed initial MRI results from 146 patients with MS from a multicenter retrospective study. Visualization of the symptomatic lesion was used as a primary criterion. Secondary criteria included one suggestive lesion (SL) aspect or topography on MRI, or one non-specific lesion associated with positive CSF. The proposed criteria led to a positive diagnosis of MS in 100 % of cases, from information available from the time of the first MRI for 145 patients (99.3 %). At least one SL was observed for 143 patients (97.9 %), and positive CSF for the 3 others. Compared to the McDonald criteria, the proposed criteria had 100 % sensitivity, with a significantly shorter mean time to reach a positive diagnosis. Furthermore, the simultaneous presence of corpus callosum, temporal horn, and ovoid lesions was associated with radiological or clinical activity after a year of follow-up. The proposed diagnostic criteria are easy to apply, have a good sensitivity, and allow an earlier diagnosis than the 2010 McDonald criteria. Nevertheless, prospective studies are needed to establish specificity and to confirm these findings.

Many years ago there was no rush to give a diagnosis of MS, because there was nothing to give treatment-wise. However this has now changed and there are options available at least for our non-UK Neuros who have no problem treating during clinically isolated syndrome.Therefore, there is an advantage to detect and diagnose MS as quickly as possible. Diagnosis used to be clinical with disease in "time" and "space" according to the Poser criteria. Then we put MRI into the mix and this is capable of spotting lesions in time and space with one scan. We had the MacDonald criteria and then the Barkhof criteria which brought imaging into diagnostic criteria. This study suggests a further modification and can spot MS after one scan because the Old MacDonald criteria are not so much E-I-E-I-O but they miss a lot, so the diagnosis may not be certain. Maybe it possible to be 100% certain off finding MS by these criteria and cut the time to diagnosis. Will these catch on? and who gets to name the criteria?

IMPORTANCE

Cerebrovascular reactivity (CVR) is an inherent indicator of the dilatory capacity of cerebral arterioles for a vasomotor stimulus for maintaining a spontaneous and instant increase of cerebral blood flow (CBF) in response to neural activation. The integrity of this mechanism is essential to preserving healthy neurovascular coupling; however, to our knowledge, no studies have investigated whether there are CVR abnormalities in multiple sclerosis (MS).

OBJECTIVE

To use hypercapnic perfusion magnetic resonance imaging to assess CVR impairment in patients with MS.

DESIGN, SETTING, AND PARTICIPANTS

A total of 19 healthy volunteers and 19 patients with MS underwent perfusion magnetic resonance imaging based on pseudocontinuous arterial spin labeling to measure CBF at normocapnia (ie, breathing room air) and hypercapnia. The hypercapnia condition is achieved by breathing 5% carbon dioxide gas mixture, which is a potent vasodilator causing an increase of CBF.

MAIN OUTCOMES AND MEASURES

Cerebrovascular reactivity was calculated as the percent increase of normocapnic to hypercapnic CBF normalized by the change in end-tidal carbon dioxide, which was recorded during both conditions. Group analysis was performed for regional and global CVR comparison between patients and controls. Regression analysis was also performed between CVR values, lesion load, and brain atrophy measures in patients with MS.

CONCLUSIONS AND RELEVANCE

Our quantitative imaging findings suggest impairment in functional cerebrovascular pathophysiology, by measuring a diffuse decrease in CVR, which may be the underlying cause of neurodegeneration in MS.This piece of research is a game-changer in my books; I don't think I quite appreciated how complex this disease is until I came across this article last night!Not only have we to contend with a frankly a confused immune system, but we now also have to think about strategies to combat brain hypoxia (the lack of oxygen) and ischaemic injury (lack of oxygen leading to areas of stroke) caused by the presence of vascular abnormalities observed in MS (see figure below). The authors may be onto something here, and large scale brain hypoxia may be the penultimate factor/missing link in the spiraling trajectory towards brain atrophy in MS.

Figure: The mean gray matter cerebrovascular reactivity (CVR) maps of the control group (top) and multiple sclerosis group (bottom) show the diffuse decrease of CVR in the patients with multiple sclerosis. The color bar shows the range of CVR values (white=good CVR, black=poor CVR).

They postulate that abnormalities in CVR observed in MS may be the result of vascular (i.e. the vessel wall) habituation to nitric oxide (which results in vessel wall dilatation) produced during the chronic inflammatory process, ultimately leading to narrowing of blood vessels. But, I don't think this is the cause in entirety. This theory ignores the fact that the vessel wall (aka endothelium) also locally produces factors that regulate blood vessel tone, and the role of blood pressure, which is the largest regulator of perfusion to vital organs. It is clear more work is needed in this area. And no CCSVI has no role here.

Monday, 23 February 2015

Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells.,Weider M, Wegener A, Schmitt C, Küspert M, Hillgärtner S, Bösl MR, Hermans-Borgmeyer I, Nait-Oumesmar B, Wegner M. PLoS Genet. 2015;11(2):e1005008. Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dorsal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.

SOX10 has nothing to do with Socks but it is a factor that turns the production of other proteins on. This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of what a stem cell will be come. The encoded protein may act as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a shuttle protein in the nucleus and is important for neural development. Mutations in this gene are associated withWaardenburg-Shah and Waardenburg-Hirschsprung disease.

Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix transcription factor encoded by theOlig2 gene. The protein is of 329 amino acids in length, 32kDa in size and contains 1 basic helix-loop-helix DNA-binding domain. It is one of the three members of the bHLH family. The other two members are OLIG1 and OLIG3. The expression of OLIG2 is mostly restricted in CNS, where it acts as both an anti-neurigenic and a neurigenic factor at different stages of development. OLIG2 is well known for determining motor neuron and oligodendrocyte differentiation, as well as its role in sustaining replication in early development.Yet more information on myelination and yet more ways to do it

PML Risk Infographic

Holistic Management of MS ver. 7.0

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